Schizophrenia is a major mental disorder that strikes in young adulthood and that has a heritability of 80-90%. Even with state-of-the-art treatment, schizophrenia often produces lifelong disability, creating a pressing need to delineate the heritable components so as to enable better classification, prognostication, and treatment. Despite the performance of many gene discovery studies, the genetic and phenotypic complexities of schizophrenia have largely confounded these efforts. To address this impasse, we will examine the etiology of schizophrenia by integrating exhaustive, high-quality genomic, phenotypic, and structural brain imaging data in a set of novel and imaginative aims. The strength of the application rests on the unique richness of our samples and the expertise of our investigative team. We bring together not just one, but two large, independent samples of individuals with schizophrenia and normal controls who have been scanned with high-resolution magnetic resonance brain imaging, exhaustively phenotyped, and who have provided DNA for genetic studies. Of these resources, it is the DNA that has yet to be fully utilized. By analyzing the DNA with state-of-the-art methods and a carefully crafted plan, we will substantially enhance the value of all the data domains. The research team comprises investigators with long histories of productivity in all pertinent areas-schizophrenia phenomenology, brain imaging, genomic technology, and biostatistics-and they are linked by a history of productive interaction and collaboration. PUBLIC HEALTH RELEVANCE: Schizophrenia is a major mental disorder that is caused primarily by genetic factors and that is also associated with brain structure abnormalities. This study will attempt to identify schizophrenia susceptibility genes by using a wide array of genomic technology-microarrays, tests for genomic copy number variations, and others-and relating the resultant genetic data in an integrated fashion to both brain structure volumes and the core disorder itself.